A first aspect of the present invention, which was originally disclosed in application Ser. No. 825,287, relates to a process for preparing ethyl-.alpha.-(1-carboxyethyl)amino-.gamma.-oxo-.gamma.-phenylbutyrate, especially its optically active (.alpha.S,1S)-form having the formula (I): ##STR1## wherein the asterisk represents the (S)-configuration at the asymmetric carbon atom.
The compound having the formula (I) is a precursor of ethyl-(.alpha.S,1S)-.alpha.-(1-carboxyethyl)amino-.gamma.-phenylbutyrate having the formula (III): ##STR2## wherein the asterisk represents the (S)-configuration at the asymmetric carbon atom, which is a very useful intermediate compound for synthesis of the various amino acid derivatives having the formula (II): ##STR3## like, and the asterisk represents the (S)-configuration at the asymmetric carbon atom, said amino acid derivatives having the general formula (II) being expected to be useful as antihypertensive agents due to their angiotensin converting enzyme (ACE) inhibitory activity.
Hitherto, it has been known that ethyl-.alpha.-(1-carboxyethyl)amino-.gamma.-oxo-.gamma.-phenylbutyrate can be prepared by subjecting ethyl-.beta.-benzoylacrylate (IV) and the (S)-alanine benzyl ester (V) to the so-called Michael addition reaction in the presence of triethylamine and then conducting hydrogenolysis of the product to cleave the benzyl group (Japanese Unexamined Patent Publication No. 103364/1983, U.S. Pat. No. 4,727,160 and Tetrahedron Letters, Vol. 25 (11), 1143, (1984)). The reaction scheme is as follows: ##STR4##
It is also confirmed that the (.alpha.S,1S)-diastereoisomer (VI) is predominantly produced when the (S)-alanine ester is employed, and thus the (.alpha.S,1S)-diastereoisomer (VI) can be obtained by crystallization or silica gel column chromatography. However, the above method employing the (S)-alanine ester requires a procedure for converting the amino group moiety of the ester, which is present in the form of a salt with an acid used in the esterification, into a free amino group, in addition to a procedure for esterifying the (S)-alanine. Further, it is required to employ such an ester that the ester moiety is selectively converted into a carboxylic group by hydrogenolysis without converting the ethyl ester moiety of the product derived from ethyl-.beta.-benzoylacryrate into a carboxylic group. Thus the ester which can be employed in the reaction is limited to esters such as benzyl ester of tert-butyl ester, which are prepared by a relatively complicated procedure. Moreover, in order to carry out a selective ester degradation, a complicated procedure such as hydrogenolysis or trifluoroacetic acid treatment is required. Consequently, it is understood that the method is not suitable for industrial production of (.alpha.S,1S)-ethyl-.alpha.-(1-carboxyethyl)amino-.gamma.-oxo-.gamma.-phen ylbutyrate, from the viewpoint of operability and cost of production.
As the result of the present inventors' continuous efforts to develop an economical, simple and efficient process for industrial production of (.alpha.S,1S)-ethyl-.alpha.-(1-carboxyethyl)amino-.gamma.-oxo-.gamma.-phen ylbutyrate, it was found that ethyl-.alpha.-(1-carboxyethyl) amino-.gamma.-oxo-.gamma.-phenylbutyrate can be obtained in an extremely high yield by reaction an alkali metal salt, an alkaline earth metal salt or a quarternary ammonium salt of alanine with ethyl-.beta.-benzoylacrylate, that the (.alpha.S,1S)-diastereoisomer of ethyl-.alpha.-(1-carboxyethyl) amino-.gamma.-oxo-.gamma.-phenylbutyrate is predominantly formed over the (.alpha.R,1S)-diastereoisomer by conducting the reaction under particularly controlled reaction conditions employing a metal salt of (S)-alanine, that the (.alpha.S,1S)-form is selectively crystallized only by adding an equivalent amount of an acid for neutralization, and the almost pure (.alpha.S,1S)-form is obtained by a simple procedure with an excellent high yield, and that ethyl-.alpha.-(1-carboxyethyl)amino-.gamma.-phenylbutyrate can be prepared by catalytically reducing ethyl-.alpha.-(1-carboxyethyl) amino-.gamma.-oxo-.gamma.-phenylbutyrate.
A second aspect of the present invention, which was originally disclosed in application Ser. No. 028,939, aims at preparing in an industrially advantageous manner an N.sup.2 -[1-(S)-carboxy-3-phenylpropyl]-L-lysine derivative which is a useful intermediate for preparing N2-[1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline having the formula (VIII): ##STR5## wherein the asterisk (*) represents the (S)-configuration with respect to the asymmetric carbon atom, which is expected to be useful as an antihypertensive agent because the proline has an excellent angiotensin converting enzyme (ACE) inhibitory activity.
In a known process for preparing N.sup.2 -(1-carboxy-3-phenylpropyl)-L-lysine derivatives, ethyl-.beta.-benzoylacrylate (IV) is reacted with the L-lysine ester derivative, N.sup.6 -benzyloxy-carbonyl-L-lysine benzyl ester (IX), by the so-called Michael addition reaction in the presence of a catalytic amount of triethylamine to give a diastereomeric mixture of the N.sup.2 -(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N.sup.6 -benzyloxycarbonyl-L-lysine benzyl ester (X), from which the N.sup.2 -(1-(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N.sup.6 -benzyloxycarbonyl-L-lysine benzyl ester (X-a) having the desired configuration is obtained by crystallization, the ester (X-a) being subjected to catalytic reduction with a palladium/carbon catalyst to give N.sup.2 -( 1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysine (XI), followed by reaction with chloroformic acid benzyl ester in order to protect the amino group at the side chain of the lysine, and purification of the product by silica-gel chromatography to give N.sup.2 -(1-(S)-ethoxycarbonyl-3-phenylpropyl)-N.sup.6 -benzyloxycarbonyl-L-lysine (XII), as shown in the following reaction scheme (Japanese Unexamined Patent Publication No. 103364/1983 and U.S. Pat. No. 4,727,160): ##STR6##
However, the above method employing the L-lysine ester derivative requires a procedure for converting the .alpha.-amino group moiety of the N.sup.6 -benzyloxycarbonyl-L-lysine benzyl ester, which is present in the form of a salt with an acid used in the esterification, into a free amino group, in addition to a procedure for esterifying the L-lysine derivative. Further, it is required to employ an ester such that the ester moiety is selectively converted in to a carboxylic group without converting the ethyl ester moiety of the product derived from ethyl .beta.-benzoylacrylate into a carboxylic group. Thus the ester which can be employed in the reaction is limited to esters such as benzyl ester or tert-butyl ester, which are prepared by a relatively complicated procedure. Since lysine is a basic amino acid having an amino group at the side chain, it is preferred that the amino group at the .epsilon.-position is protected by the protective group usually employed in the peptide synthesis in order to carry out the reaction of the amino group only at the .alpha.-position. When a benzyloxycarbonyl group is employed as the protective group, the amino group at the .epsilon.-position is deprotected by hydrogenolysis in the reduction of the compound (X-a) to the compound (XI). In order to use the compound (XI) in the subsequent reaction, the amino group at the .epsilon.-position in the lysine moiety is preferably protected, and thus the compound (XI) is reacted with the chloroformic acid benzyl ester to introduce a benzyloxycarbonyl group. However, since the amino group at the .alpha.-position is reactive as well as the amino group at the .epsilon.-position in the lysine moiety in the compound (XI), the production of by-product inevitably occurs. Therefore, the molar yield of the compound (XII) purified by silica gel chromatography is as low as 42% based on the compound (XI), and also the total molar yield is only 15.8% based on the starting N.sup.6 -benzyloxycarbonyl-L-lysine benzyl ester. As mentioned above, the method gives a quite low yield with the employment of starting materials which are prepared in many steps and is not well suited for the production of the N.sup.2 -(1-carboxy-3-phenylpropyl)-L-lysine derivative on an industrial scale, from the viewpoint of operability and economy.
As a result of the inventors' research, in light of the above-mentioned technical background, the inventors have now been found that an N.sup.2 -[1-carboxy-3-oxo-3-phenylpropyl]-L-lysine derivative having the formula (XIII): ##STR7## wherein R.sup.1 is an alkyl group and R.sup.2 is an acyl or urethane type protecting roup, can be obtained in extremely high yield by reacting a .beta.-benzoylacrylic acid ester having the formula (XIV): ##STR8## wherein R.sup.1 is an alkyl group, with an L-lysine derivative having the formula (XV): ##STR9## wherein R.sup.2 is an acyl or urethane type protecting group which is stable upon catalytic hydrogenolysis in the presence of a base in an amount equivalent to the compound (XV), that the desired compound with the (S)-configuration with respect to the asymmetric carbon atom can be obtained in a large amount compared with the undesired compound with the (R)-configuration, by conducting the above-mentioned reaction under specific reaction conditions, and that an N.sup.2 -(1-carboxy-3-phenylpropyl)-L-lysine derivative having the formula (XVI): ##STR10## wherein R.sup.1 and R.sup.2 are as defined above, can be easily prepared by conducting catalytic hydrogenolysis of the lysine derivatives (XIII).